1. Field of the Invention
The present invention relates to a pharmaceutical composition for the prevention and treatment of liver toxicity comprising TNP (N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine) or a pharmaceutically acceptable salt of the same as an active ingredient and a health functional food comprising the same.
2. Description of the Related Art
TNP (N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine) is a commercialized chemical, which is known as the inositol pentakisphosphate kinase specific inhibitor (J Biol Chem. Apr. 17, 2009; 284(16): 10571-10582). TNP inhibits the biosynthesis of 5-inositol pyrophosphate, by which TNP down-regulates intracellular 5-inositol polyphosphate and at the same time increases insulin signaling in liver cells (Cell. 2010; 143(6): 897910). When TNP is treated to bone marrow derived mesenchymal stem cells, it can delay the progress of cellular aging (Stem Cell Res Ther. 2014 Mar. 26; 5(2):33). However, it is unknown whether or not TNP has the effect of preventing or treating acute liver toxicity.
Acetaminophen (AP), which is well known as Tylenol, has been developed in USA in 1950s. This drug is one of the most used drugs that has been world-widely used as a pain killer and a fever reducer (domestic Tylenol sales a year is approximately 25 million dollars). The chemical name of Tylenol is N-acetyl-p-aminophenol and is also called paracetamol (Dargan P I et al., Crit Care. 2002 6(2):108-10). The acceptable dose of acetaminophen is 150 mg/kg/day, and maximum 4 g can be orally administered to an adult for a day. So, it is classified as a safe OTC (over the counter) drug that can be sold without doctor's prescription. However, if acetaminophen is over-used, fulminant hepatic failure, liver necrosis, nephrotoxicity, and liver cirrhosis, or even death can be caused. So, it can be said that this drug has a double-sided character.
The mechanism of liver toxicity is that acetaminophen turns into a cell-killing reactive material mediated by a hepatic oxidase. In general, when such a reactive material is generated, it is detoxified without causing a problem. But, the excessive dose of such a material consumes all the endogenous antitoxic materials, leading to the destruction of liver cells. Particularly, when acetaminophen is administered at a low concentration, it binds to non-toxic glucononic acid and sulfate, resulting in the detoxified conjugate, and then it is excreted through bile or blood plasma. And 5˜10% of the administered acetaminophen is metabolized by P450 (CYP) particularly by CYP2E1 (Ray S D et. al., J Pharmacol Exp Ther. 1996; 279:1470-83). That is, acetaminophen is changed into N-acetyl-p-benzoquinoneimine (NAPQI) in the liver, and the converted metabolite binds to glutathione and at this time this conjugate does not show toxicity (Hazai E, et al., Biochem Biophys Res Commun. 2002; 291(4):1089-1094.). However, when the excessive dose of acetaminophen is taken in the liver, it binds to glucononic acid and sulfate with loosing detoxification ability and as a result highly reactive NAPQI is accumulated, by which cell membrane is critically damaged to induce apoptosis of liver cells that cannot be recovered and instead causes liver toxicity or even death (Webster P A et. al., J Clin Pharmacol. 1996; 36:397-402; Albano E et. al., Mol Pharmacology. 1985; 28:306-11; Kyle M E et. al., Biochem Biophys Res Commun. 1987; 149:889-94 Mahadevan S B et. al., Arch Dis Child. 2006: 91:598-603).
The animal models for acetaminophen mediated liver injury model are represented by the mouse model and the hamster model. Similarity is found in human (Tee L B et a., Toxicol Appl Pharmacol. 83(2):294-314. 1986). Liver toxicity caused by acetaminophen increases when alcohol is taken in together. It is mandatory by FDA to notify that a patient who regularly drinks alcohol at least three glasses of alcohol daily must consult with a doctor before taking this drug because of the liver toxicity. Studies have been actively going on to develop a drug to eliminate and relieve the liver toxicity caused by acetaminophen.
The liver is a major organ responsible for detoxication and controlling blood circulation. Once the liver is injured, various diseases can be caused along with inflammatory response. So, it is very important to develop a drug that can protect the liver from being injured.
Thus, the present inventors searched and tried to identify a material that is effective in preventing and treating liver injury. As a result, the inventors confirmed that TNP known as a 5-inositol pyrophosphate inhibitor suppressed apoptosis caused by acetaminophen in human embryonic stem cell-derived liver cells, mouse liver cells, and human hepatoma cell lines, increased the concentration of glutathione converted in liver cells, and inhibited JNK phosphorylation that is a kind of response against stress increased by acetaminophen. The inventors further confirmed that TNP had the activity of protecting liver cells from the toxicity caused by acetaminophen in an animal model. At last, the inventors completed this invention by disclosing that TNP or a pharmaceutically acceptable salt thereof could be efficiently used as an active ingredient of a composition for preventing and treating liver toxicity.